Parkinson's disease is one of the most common neurodegenerative diseases, affecting about one percent of all people over the age of 65. It is characterized by rigidity, bradykinesia (reduced movement) and tremors, which are caused by the progressive degeneration of dopamine-containing neurons in a brain region called the substantia nigra. Another characteristic feature of the disease is that the brains of Parkinson's patients contain microscopic protein deposits, known as Lewy bodies. Although some cases of Parkinson's disease can be attributed to genetic risk factors, the majority of cases are still unexplained; these so-called "sporadic" cases have been proposed to result from environmental factors. In the December issue of Nature Neuroscience, Tim Greenamyre and colleagues at Emory University in Atlanta, Georgia, show that rotenone, a commonly used organic pesticide, can induce the major features of Parkinson's disease in rats. These results not only provide a new animal model for testing potential treatments, they also support the idea that chronic exposure to environmental pesticides may contribute to the incidence of Parkinson's disease in humans.

Before this study, the most realistic animal model of Parkinson's disease was the so-called MPTP model, in which mice or monkeys are treated with a drug known as 1,2,3,6-tetrahydropyridine (MPTP). This model originates from the early 1980s, when a number of heroin addicts developed sudden and irreversible symptoms of Parkinsonism after injecting themselves with an illicit drug preparation contaminated by MPTP. The reason for the toxic effect is that MPTP (or more strictly, its derivative MPP+) inhibits one of the enzymes in mitochondria, intracellular organelles that provide the cell with energy.

Rotenone, like many other pesticides, inhibits the same mitochondrial enzyme (called complex I) as MPP+, and so Greenamyre and colleagues hypothesized that chronic treatment with low levels of rotenone might produce Parkinsonian symptoms in rats. They administered rotenone intravenously over a period of several weeks, and observed gradual degeneration of the dopamine neurons, accompanied by behavioral features of Parkinsonism and the formation of structures that closely resemble Lewy bodies. A likely explanation, as yet untested, is that rotenone acts by causing the mitochondria to produce free radicals, reactive chemicals that produce oxidative damage in a variety of contexts and have been implicated in many human degenerative diseases.

Rotenone is a naturally occurring pesticide, and it is widely used both as an insecticide and as a method for killing fish (as part of water management programs). It is considered relatively benign compared to many other pesticides. Although the new study does not prove that rotenone causes Parkinsonism in humans, it is likely to raise new questions about rotenone's safety. More generally, it lends credence to the idea that chronic exposure to environmental toxins, including pesticides, may contribute to the incidence of the disease. The main risk factor for Parkinson's disease is age, and it has also been claimed, more controversially, that the disease is associated with living in rural environments. Determining to what extent pesticide exposure can account for Parkinsonism will require a great deal of further work. The present findings, however, are consistent with the idea that chronic exposure to low levels of environmental toxin may cause cumulative damage to the brain's dopamine system, eventually leading to the clinical symptoms of the disease. (From Nature Neuroscience press release.)



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